Synthesis and characterization of cyclic pseudopeptide libraries containing thiomethylene and thiomethylene-sulfoxide amide bond surrogates

Yvon Crozet, James J. Wen, Arno F. Spatola
Department of Chemistry, University of Louisville, Louisville, KY 40292, U.S.A.

Rachel O. Loo, Philip C. Andrews
University of Michigan Medical School, Protein and Carbohydrate Structure Facility, Ann Arbor, MI 48109, U.S.A.

Abstract
We describe the first examples of a series of cyclic pseudopeptide libraries that have been prepared in a systematic approach in order to facilitate both synthesis and subsequent deconvolution attempts. Our synthetic strategy involved the attachment of a trifunctional amino acid (Asp, Asn or Glu) to a polystyrene resin via its side chain, and stepwise chain elongation using either protected amino acids or a pseudodipeptide building block. Head to tail cyclic peptides were formed by removal of the temporary N- and C-terminal protecting groups followed by ring closure by amide formation. Cyclization of the hexa, hepta, and octapseudopeptides on the resin avoided dimer formation, as monitored by mass spectrometry. We utilized a ’psi-scan‘ approach in which a second fixed position was serially addressed by stepping a dipeptide surrogate, Proy[CH_2S]Gly around the rings to generate a group of cyclic pseudopeptide sub-libraries. Oxidation of y[CH_2S] to y[CH_2SO] helped validate the synthesis and also provides a strategy for forming a new set of pseudopeptide libraries (previously described as ’libraries from libraries‘). Our results suggest that libraries of cyclic pseudopeptides are an efficient method of preparing and assaying these synthetically more challenging entities as potential drug leads.

Keywords
combinatorial chemistry, cyclic peptides, libraries, pseudopeptides, solid phase synthesis, thiomethylene